The treatment of malignant mesothelioma (MPM) remains inadequate. New therapies, such as gene therapy or immuno-gene therapy, are desperately needed. This Project is based on a previous series of Phase I clinical trials using recombinant, replication-deficient adenoviral (Ad) vectors containing the Herpes Simplex Thymidine Kinase (HSVtk) gene in 34 MPM patients. Significant intratumoral HSVtk gene transfer was achieved and some radiographic and clinical responses were noted, including 2 patients who had durable complete responses in delayed fashion, highly suggestive of anti-tumor immune responses. On this basis, the focus of laboratory and clinical work was shifted to genetic immunotherapy of thoracic malignancies. Based on strong preclinical data, a new Phase I clinical trial using a single dose of intrapleural adenoviral interferon beta (Ad.lFN-beta) for patients with MPM and malignant pleural effusions (MPE) was conducted. The approach was safe and a number of immunologic responses, as well as clinical responses were observed. The goal of this Project is to continue and extend these clinical trials aimed at patients with mesothelioma. In the first aim, a Phase 1 trial will be conducted to assess the safety, toxicity profile, immune responses, and clinical effect of two intrapleural doses of Ad.lFN-beta for patients with MPE/MPM. Specific Aims 2 and 3 will consist of Phase 2 clinical trials testing approaches in patients with MPM that were developed from our preclinical studies to augment efficacy. Aim 2 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta as neo-adjuvant therapy in combination with surgical debulking and adjuvant COX-2 inhibitors in patients with MPM. Aim 3 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta in combination with chemotherapy and adjuvant COX-2 inhibitors in patients with MPM. In Aim 4, investigators will begin the steps needed to develop an adoptive immunotherapy trial using genetically engineering T-lymphocytes reactive against mesothelin for patients with mesothelioma and other tumors expressing this tumor antigen after preclinical optimization.